Dedicated to the Cargo Cults of Biology Science, Biotechnology and the Pharmaceutical Industry.
"So we really ought to look into theories that don't work, and science that isn't science"
Richard Feynman,
Cargo Cult Science,
From a Caltech commencement address given in 1974

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Friday, January 31, 2014

David Blech earned the title "The King of Biotech". Armed with a Masters degree in Music Education, he became a member of the Forbes 400 investing in companies like Genetic Systems Corporation, Icos, and Celgene. In 1990 he founded D. Blech and Co., a registered broker-dealer involved in underwriting biotechnology issues. On September 22, 1994 the company was deep in debt and ceased operations due to net capital rule violations. The day is known as Blech Thursday.

The uniform net capital rule is a rule created by the U.S. Securities and Exchange Commission ("SEC") in 1975 to regulate directly the ability of broker-dealers to meet their financial obligations to customers and other creditors. Broker-dealers are companies that trade securities for customers (i.e., brokers) and for their own accounts (i.e., dealers).

Blech was given a five year probation sentence in 1998 for criminal fraud. In May 2012 he pleaded guilty to manipulating shares of biopharmaceutical companies Pluristem Therapeutics Inc and Intellect Neurosciences Inc in 2007 and 2008. The Cargo Cult message of the story is that success in biotech financial matters does not require a PhD from MIT. It does not require bend-over-backwards scientific honesty. It requires the mind of a gambler. Remember the successes, but not the failures. Remember random events around your successes and tout them as skillful tricks of the trade you are in. In Seattle there is a building with four numbers in front.

Inside this building are people who have chosen the same career path as David Blech. Carl Weissman and Steven Quay have been at the helm of several costly biotech investment decisions. Neither has found themselves on the Forbes 400 but they have had lucrative careers in biotechnology. The investments they have attracted have not been lucrative. Weissman is now the former CEO of Accelerator and Quay is in charge of a sinking ship known as Atossa Genetics.

I don't want to go into further details about these investment opportunities. I've written about them before. Each man is a leader, as defined by the terms of a CEO. You are investing in them and the decisions they make with your money. Like David Blech, they are not scientists, as defined by the terms of a CSO. They seek money and use it to build biotechnology companies. The science is none of their business. Their careers have seen hundreds of millions come and go. They want you to focus in their ability to make the money come, never mind how it goes away.The takeaway from Blech, Weissman and Quay is that leadership matters. What makes a good biotech leader? In 1992 David Blech would have been considered a great leader. In their rise, Weissman and Quay were considered worthy of stewardship over millions and millions and the careers of many very smart people. In the ruins of their management is the loss of that money and the ruined careers of too many scientists. True, Blech (the music education master) started companies that made money and continue to do so. But he did not do the work that made these companies long term successes. These three individuals are prime examples of the short term mentality. Start company, get out before the fall. They are prime examples of why we need standardization, certified laboratories with certified lab workers. We need to create an career path for scientists who have the power of science to help investors avoid the song and dance of these three men. One of these men is in prison, one is looking for work, and one is draining $600,000 per year (CEO and CSO salaries for he and his wife) until the latest round of financing is depleted. Be assured that all three will continue to fight for their livelihood and raise money to spend on short term money making biotechnology companies. There is a little bakery on the bottom floor is 1616 Eastlake called Grand Central Baking Company. They are the most profitable company that has ever done business out of 1616 Eastlake. They have outlasted all of the Accelerator companies. They have a passion for what they do.

More than two decades after our founder Gwen Bassetti introduced the Como loaf in Seattle’s historic Pioneer Square, we are still locally owned, led by a unique mixture of family and friends, and dedicated to the craft of artisan baking.

Biotech royalty, like Bech, Weissman and Quay, have a passion for the deal. They love being the biggest boy at the big boy table. But this isn't the craft that makes biotech success stories. The craft of "the deal" has led to many a lawsuit, jail time, and high unemployment. What makes any technology company succeed is a dedication to the science and technology behind the product. For this, you need someone outside the royal families.

Friday, January 10, 2014

I would never do a PhD. I’m sorry, but the lab bench is not cut out for me. I don’t want to do academia. I want to work in the clinical field and do business or public advocacy. - Jack Andraka

When I first saw Jack Andraka on 60 Minutes running down the isle to collect his award at the Intel International Science and Engineering Fair 2012, I thought I was watching someone who had just won the Miss America pageant or a chance to bid on The Price Is Right. His demeanor was that of an attention getter. My bias is that I do not like that kind of personality. Rather I gravitate towards Feynman, who did not like awards. I gravitate towards Frederick Sanger who said, "Scientific research is one of the most exciting and rewarding of occupations." I like Einstein who said that true art and science begins where our hopes and dreams leave off. This 16 year old spent 3 months in the lab and a year on the TEDx talk circuit. He was a media darling, but was he a Cargo Cult Scientist?

I've given my bias. I will try to avoid it when making my argument.

This article from Mathew Herper in Forbes deviates from the positive spin from the popular media that greeted Jacks entry into the scientific community. The title, "Why Biotech Whiz Kid Jack Andraka Is Not On The Forbes 30 Under 30 List".

But I decided not to include Andraka on the list, overriding the recommendation of an expert judging panel, because the work was not yet published in a peer-reviewed scientific journal. It is by published work that scientists are judged. I still think this was the right decision. In fact, when Andraka volunteered to share a draft of a paper that he does plan to submit to a scientific journal, my concerns deepened.

Here are a few reasons why he is on the Cargo Cult Scientists list:

1) So we really ought to look into theories that don't work, and science that isn't science.

As Mathew Herper points out in his article, Jack Andraka has not yet published his work. Many scientists that reviewed an early version had their doubts about some of the claims. The question science asks, "Does the theory work?" We don't know.

2) Now it behooves me, of course, to tell you what they're missing. But it would be just about as difficult to explain to the South Sea islanders how they have to arrange things so that they get some wealth in their system. It is not something simple like telling them how to improve the shapes of the earphones. But there is one feature I notice that is generally missing in cargo cult science. That is the idea that we all hope you have learned in studying science in school--we never say explicitly what this is, but just hope that you catch on by all the examples of scientific investigation.

Jack Andraka is a young man with little experience in science. Something is missing in his foray into science.

3) Details that could throw doubt on your interpretation must be given, if you know them. You must do the best you can--if you know anything at all wrong, or possibly wrong--to explain it. If you make a theory, for example, and advertise it, or put it out, then you must also put down all the facts that disagree with it, as well as those that agree with it.
Mathew Herpers article highlights some critical details that others have had to point out that throw doubt onto Jack and his mentors interpretation of the lab work.

Andraka’s “168 times faster, 26,667 times less expensive, and 400 times more sensitive” figures are based on a comparison with ELISA. But Church saw problems with the way that Andraka characterizes the ELISA test.

Test speed: Andraka says he compared the speed of his test to the amount of time he spent trying to get results from an ELISA kit he ordered online: 14 hours. But usually a modern ELISA test takes 1 hour.

Test cost: Andraka is comparing the commercial cost for a test – including the manufacturer’s profit and overhead – to his own materials cost. That’s not a fair comparison. He says the only mesothelin test that he found cost $912 per kit. But other ELISA tests are for sale online for $400 per 60 tests or $600 for 96 tests – in other words, about $6.50 per test run. That still compares favorably to Andraka’s $3 per 10 tests, but remember that there would also be a commercial markup if a company decided to sell his tests.

4) In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.
Since the work of Jack Andraka has not been published, we need more information. His mentor, the media and the public all want to believe we have a genius in the wings. The stories and awards provide us with the information and judgement in one particular direction. The truth might fall short of this story.

I agree with Mathew Herper, it was a pretty neat thing for a teenager to do. To take an interest in biotechnology and cancer detection at 15 is remarkable. The tenacity to present his idea to a hundred scientist before getting the attention of one is why I think the kid is going places. His science probably won't go nearly as far.

Which leads me to the conclusion that the boy has merely been a pawn in the Cargo Cults of Biotechnology. His mentor did not discourage the boy nearly as much as those meanies who came later. But that is how science must work. The truly talented scientists have a passion for this pursuit. They do what they do because they are good at it. They want to work in a laboratory, design experiments, observe what happens, and live a life learning new things that no one else has thought of yet. The details that separate science from Cargo Cult Science are subtle, often times the cause of eye rolling among non-scientists. Where some will say, "big deal" a scientist will demonstrate just how big of a deal a seemingly small detail can be. These people are often introverted, soft spoken, and more focused on petri dishes than their own reputation.

As one commenter said from the Forbes article: "Based on your description, the kid sounded pretty promotional. I don’t know if he will become a scientist. I have a feeling he may become one of those slick biotech CEO in a few years."A scientist is not a CEO of a biotech company, a bureaucrat at the NIH, or a judge of a science fair. A scientist might hold one of these titles, but the titles do not make you a scientist. Each title may require the holder to have a PhD. But science is bigger than titles and awards and the people who strive for them. A scientist is merely a life long student of the natural world that still has a billion secrets left for us to figure out.

The concept that science must be reproducible before you can call it science is a slippery slope to some. A comment from the Nature webpage listed above:

The claims presented here are pretty outlandish. Particularly relevant to "Hematology and Oncology" we now know that mice housed under different conditions with different microflora can have vastly different outcomes in any model, not just cancer. To suggest academic incompetence or outright unethical behavior is offensive, and is a particularly narrow view of why experiments are difficult to reproduce. Further, as indicated in Table 1, the entire definition of not-reproducible hinges on a priori profit motive of "robust" differences (whatever that means). There is always room for improvement in science, but this entire article is disingenuous and belittling to those of us who are on the front lines.

Here is the enemy. Feynman described the mouse maze experiment where confounding factors lead many researchers astray. Finding out where we can go astray is an important part of the scientific method. If you don't rule out as many confounding factors, you are subject to making mistakes like those made by not knowing the effect of microflora on mouse experiments. Will a study on microflora get you a tenured position or will it make you a thorn in the side of the scientists who are more concerned about their career in cancer research? Most likely the latter is true. It is the responsibility of leadership to create a more welcoming place for real science, that may not jibe with the career/corporate aspirations of less rigorous scientists.

It is important to realize that this debate, highlighting the deficiencies our scientific process, is taking place openly within the scientific community. This is a sign of the strength of our scientific system.

That is a very important point. People are embracing the conversation about our shortcomings in science. We need more humility, more honesty and less arrogance. A call for increasing the rigors of our soft science is only going to be a positive for the good name of science. The people who will be hurt by a push in the direction of the scientific method are those who do not appreciate what it can do.

The above commenter may believe that any dissenting view of modern science is heresy. (I don't want to create a straw-man argument, thus he may...) If the argument against increasing reproducibility, increasing transparency, and increasing rigor, is that it would make working in science too hard, then I would argue that the power of real science is misunderstood. Your boss may want to see a positive result from your mouse study on his desk prior to his/her next board meeting. You may have just discovered that the microflora is confounding the reproducibility of your experiments. What do you do? Is it wise to assume that everyone believes that the newfound knowledge of the microflora will be received with open arms from the guy who didn't ask you to look into such details? In this case, the scientific method is in opposition to the political method. The Machiavellian tactics you employ to advance or simply to keep your job are often times jeopardizing future research, yours and those in your field.

The questions Glenn Begley asks:

What constitutes reproducibility?
What, if anything, has changed?
What is driving this?
What is being done and where will this take us?

What Glenn Begley is doing is very important for others who currently work in, or one day hope to work in science.

The majority of scientific discoveries in the biomedical sphere should be sufficiently rigorous and robust to allow other investigators to build on that work and move the field forward. Hopefully the changes instituted as a result of this debate will help further strengthen our discovery processes. - Glenn Begley

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My biotech career is merely a dream. In this dream we are all living on an Island where our ancestors once watched the westerners develop drugs that helped their people fight off disease and suffering. The westerners left and we are now donning their white lab coats and trying to create the drugs ourselves. We have their books, labs, beakers and a handful of drug targets they left behind. But nothing is working.